Poor regeneration of retinal ganglion cell (RGC) axons is a major obstacle for treating ocular trauma and diseases including glaucoma. There are as yet no therapies to repair optic nerve once the damage is done. We now demonstrate that modulation of PTEN (phosphatase and tensin homolog) expression in adult RGCs using small interference RNAs (siRNA), with elevation of ciliary neurotrophic factor (CNTF) and cyclic AMP (cAMP) promotes robust optic nerve regeneration. Remarkably, some regenerating axons successfully reach a brain target, the suprachiasmatic nucleus (SCN), a master pacemaker for regulating circadian rhythms. The overall goal of this proposal is to determine; i) whether the axons that reach to the SCN form functional connections and induce recovery of circadian rhythm, and ii) develop strategies to further enhance optic nerve regeneration to the central targets. Despite impressive regeneration, not all retinal neurons regenerated their axons over long distances, and many regenerating axons stalled at the optic chiasm. In Aim 1, we will combine strategies to enhance the intrinsic growth potentials of RGCs to further increase regeneration. Next, we will look for factors that limit axon regeneration into and beyond the optic chiasm. Recently, we found that over-expression of light sensor proteins induces some axon regeneration. In Aim 2, we will elucidate the molecular mechanisms underlying this form of regeneration. It is unknown whether the regenerated axons in the SCN restore the ability of the SCN to adjust to light dark cycles, a process known as circadian photoentrainment. In Aim 3, we will determine whether the axons that reach to the SCN form functional connections and induce recovery of circadian photoentrainment. Identifying methods to further increase regeneration to brain and determining whether the regenerated axons restore visual functions represent critical future studies. Results obtained from these studies will provide invaluable information on developing future therapies to repair degenerated optic nerve after glaucoma and traumatic optic neuropathy.